Polyamines have been implicated in many aspects of cell division. Impairment of the biosynthesis of polyamines by means of enzyme inhibitors is believed to cause a decrease in cell proliferation in mammals. Although the physiological role of polyamines has not been clearly delineated, there is evidence to suggest their involvement with cell division and growth, H. G. Williams-Ashman et al., The Italian J. Biochem. 25, 5-32 (1976), A. Raina and J. Janne, Med. Biol. 53, 121-147 (1975) and D. H. Russell, Life Sciences 13, 1635-1647 (1973).
Polyamines are also known to be essential growth factors for certain microorganisms, as for example E. coli, Enterobacter, Klebsiella, Staphylococcus aureus, C. cadaveris, Salmonella typhosa and Haemophilus parainfluenza. There is evidence to suggest that polyamines are associated with both normal and neoplastic mammalian cell growth, there being an increase in both the synthesis and accumulation of polyamines following a stimulus causing cellular proliferation. It is also known that there is a correlation between polyamine formation and the activity of the decarboxylase enzymes of ornithine, S-adenosylmethionine, arginine and lysine. The term polyamine is taken to include the diamine putrescine and the polyamines spermidine and spermine. Putrescine is the decarboxylation product of ornithine, catalyzed by ornithine decarboxylase. Putrescine formation may also occur by decarboxylation of arginine to form agmatine, which is hydrolyzed to give putrescine and urea. Arginine is also involved in ornithine formation by action of the enzyme arginase. Activation of methionine by the enzyme S-adenosylmethionine synthetase forms S-adenosylmethionine which is decarboxylated. The propylamine moiety of the activated methionine may then be transferred to putrescine to form spermidine. Alternatively, the propylamine moiety may be transferred to spermidine to form spermine. Hence, putrescine serves as a precursor to spermidine and spermine. Additionally, putrescine has been shown to have a marked regulatory effect upon the polyamine biosynthetic pathway. Also an increased synthesis of putrescine has been shown to be an early indication that a tissue will undergo renewed growth processes. Cadaverine, which is the decarboxylation product of lysine, has been shown to stimulate the activity of S-adenosylmethionine decarboxylase and is known to be essential to the growth processes of many microorganisms, for example, H. parainfluenza.
The rationale of polyamine metabolism has been suggested by Cohen, Science 205, 964 (1979). The apparent unique role of polyamine metabolism in trysanosomes and the dependence of trysanosomes upon ornithine decarboxylase as a source of putrescine further supports our observations that certain specific ornithine decarboxylase inhibitors of polyamine synthesis are highly effective in inhibiting the growth of protozoa.